1. Field of the Invention
The present invention relates to an improved method for manufacturing dipeptidyl peptidase-IV inhibitor and an intermediate.
2. Description of the Related Art
DPP-IV is an enzyme functioned as a cleavage of N-terminal dipeptide of peptide having a terminal sequence of H-Xaa-Pro-Y (or H-Xaa-Ala-Y, where Xaa is any lipophilic amino acid, Pro is proline, and Ala is alanine) (Heins J et al. Biophys Acta 1988; 161), and also called DP-IV, DP-4, or DAP-IV. After finding out that DPP-IV degrades glucagon-like protein-1 (hereinafter, called as to GLP-1) that is known to have a powerful effect on a control function of insulin to blood glucose contents after dinner (Mentlein R et al. Eur J Biochem 1993:829-35), a possibility as very powerful therapeutic agent for Type II diabetes is presented, and then a study for developing DPP-IV inhibitor has become faster.
Merck Company developed triazolo piperazine compound with beta-amino acid structure, sitagliptin, during an investigation about DPP-IV inhibitor. The compound is the first DPP-IV inhibitor for treating Type II diabetes and has now become commercially available under a trademark, Januvia™, around the world after obtaining the new medicine approval from U.S. FDA in 2006. On this matter, Korean Patent Publication No. 2008-0094604 discloses that when triazolo piperazine part of sitagliptin is substituted with piperazinone containing hetero atom, it has an excellent DPP-IV inhibition activity, and also a significantly improved bioavailability as compared to that of the conventional DPP-IV inhibitor; and provides a heterocyclic compound containing new beta-amino group represented by the following Chemical Formula 1, or pharmaceutically acceptable salt thereof, a method for manufacturing the same, and a pharmaceutical composition, which contains the same as an effective component, for preventing and treating diabetes or obesity.

(In the above Chemical Formula 1, X is OR1, SR1 or NR1R2, where R1 and R2 are a lower alkyl of C1-C5, respectively; and in NR1R2, R1 and R2 may be 5-membered ring to 7-membered ring containing hetero atom, O.)
As shown in the following Reaction Formula A, Korean Patent Publication No. 2008-0094604 discloses a method for manufacturing heterocyclic compound represented by Chemical Formula 1 with beta-amino group, the method comprising I) preparing a compound represented by Chemical Formula 4 bonded with peptide bond by reacting a compound with beta-amino group represented by Chemical Formula 2 and a substituted heterocyclic compound represented by Chemical Formula 3 using 1-hydroxybenzotriazol (HOBT), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), and tertiary amine; and II) reacting the compound represented by Chemical Formula 4 under an acid condition:

(In the above Reaction Formula A, X is the same as defined in the above Chemical Formula 1.)
At this time, the compound with beta-amino group represented by Chemical Formula 2 in the above Reaction Formula A may be used for manufacturing various DPP-IV inhibitors as disclosed in International Laying-Open Gazettes WO03/000181, WO03/004498, WO03/082817, WO04/007468, WO04/032836, WO05/011581, WO06/097175, WO07/077,508, WO07/063,928, WO08/028,662, WO08/087,560, and the like, besides the production of DPP-IV inhibitor represented by the above Chemical Formula 1, and may be produced through various methods.
For example, the compound represented by the above Chemical Formula 2 may be produced by using the method as disclosed in J. Med. Chem. 2005; 141 and Synthesis 1997; 873 as shown in the following Reaction Formula:

Specifically, ester compound is obtained through an amine-protecting reaction after reacting (25)-(+)-2,5-dihydro-3,6-dimethoxy-2-isopropylpirazine with 2,4,5-trifluorobenzyl bromide and acid-treating. The ester compound may be again hydrolyzed to obtain 3-(2,4,5-trifluorophenyl)-2-aminopropionic acid; then diazoketone may be formed by using isobutyl chloroformate, tertiary amine such as triethyl amine or diisopropylethyl amine, and diazomethane; and the compound represented by Chemical Formula 2 may be produced by reacting the diazoketone with silver benzoate. However, the reaction as mentioned above has problems that it should be performed at low temperature (−78° C.), or should use an expensive alpha-amino acid and highly risky diazomethane.
Other method for manufacturing the compound represented by the above Chemical Formula 2 is also known in Tetrahedron: Asymmetry 2006; 205 or similarly Bioorganic & Medicinal Chemistry Letters 2007; 2622, as shown in the following Reaction Formula:

That is, 2,4,5-trifluorophenyl acetic acid is activated using 1,1′-carbonyldiimidazole, and then reacted with mono-methyl potassium malonate to produce beta-keto ester compound. The beta-keto ester compound is reacted with ammonium acetate and ammonium aqueous solution to produce enamine ester, and the ester compound is then reacted with chloro(1,5-cyclooctadiene)rhodium (I) dimer and chiral ferroceny ligand I through a high-pressure hydrogen reaction to produce the compound that is a beta-amino ester having chiral primary amine only. And then, the compound may be hydrolyzed to produce the compound represented by Chemical Formula 2. However, the above-described method has problem that the high-pressure hydrogen reaction should be performed by using an expensive metal catalyst.
In addition, the method for manufacturing the compound represented by Chemical Formula 2 is also disclosed in International Patent Publication No. WO 04/87650.

Specifically, 2,4,5-trifluorophenyl acetic acid is reacted with 2,2-dimethyl-1,3-dioxane-4,6-dione and oxalyl chloride that are an acid activation reagent and then the resulting product is refluxed in methanol to produce a compound corresponding thereto. The corresponding compound is reacted with (s)-BINAP-RuCl2 that is a reduction reagent with enantioselectivity through a hydrogen reaction to produce a compound with (S)-coordination, and then the resulting compound is again hydrolyzed and then is coupling-reacted with O-benzylhydroxyamine to produce an intermediate. The intermediate produced as mentioned above may be subjected to a ring condensation reaction in the presence of triphenylphosphine and diisopropylazodicarboxylate and treated with lithium hydroxide aqueous solution to produce the compound represented by Chemical Formula 2 with (R)-coordination also in which an amine group is protected with O-benzyl. However, the above method has a problem that an overall process is long and tedious so that the yield of reaction is low and the reaction should be performed for a long period.
As mentioned above, the conventionally known method for manufacturing the compound represented by Chemical Formula 2 has several problems such as use of an expensive reagent, long synthesizing time, and low yield, and thus it is not sufficient for a commercial mass-production.
Furthermore, the compound represented by Chemical Formula 3 may be produced by using the following Reaction Formula as disclosed in Korean Patent Publication No. 2008-0094604:
                (In the above Reaction Formula, X is the same as defined in the Chemical Formula 1.)        
Specifically, D-serine methyl ester compound, which is a starting material, is substituted with trityl chloride; then hydroxyl group is again substituted with mesyl group, and then refluxed to convert to aziridine compound.
The trityl group is removed from the aziridine compound by using trifluoroacetic acid; then the aziridine compound is protected with benzyloxycarbonyl (Cbz), and then is reacted with HX; and Cbz is de-protected to obtain methyl 2-amino-3-substituted carbonate. The intermediate may be produced by using the compound produced by protecting the secondary amine of the compound produced through reacting N-butyloxycarbonyl-2-amino acetaldehyde with a reduction reagent (sodiumcyanoborohydride, sodiumtriacetoxyborohydride, sodiumborohydride, and the like) and the compound, of which secondary amine is protected with benzyloxycarbonyl (Cbz), and the compound of which butyloxycarbonyl (Boc) is de-protected. The compound produced as mentioned above is subjected to a cyclization with trimethyl aluminum (or diisopropylethylamine/ethanol, sodium hydrogen carbonate/methanol, and the like) to de-protect Cbz so that the compound represented by Chemical Formula 3 may be obtained.
However, the above method has a problem that it also uses an expensive reagent, the time for synthesizing is long, and the yield is low so that it is not suitable for a commercial mass-production.
Furthermore, since 1-hydroxybenzotriazol (HOBT) and 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) used for producing the conventional compound represented by Chemical Formula 1 are an expensive reagent, the cost for reaction is high so that it is not suitable for a commercial mass-production.
For this reason, the present inventors completed the present invention by confirming that the compound represented by Chemical Formula 1 can be economically produced with high yield by using the new method for manufacturing the compounds represented by Chemical Formula 2 and Chemical Formula 3 used with cheaper reagents during the study for a manufacturing method suitable for a commercial mass-production, in which the method uses cheaper reagents; is an economical method; and improves a yield.